Butyrate, a metabolite produced by gut bacteria, has demonstrated beneficial effects in the colon and has been used to treat inflammatory bowel diseases. However, the mechanism by which butyrate operates remains incompletely understood. Given that oral butyrate can exert either a direct impact on the gut mucosa or an indirect influence through its interaction with the gut microbiome, this study aimed to investigate three key aspects: (1) whether oral intake of butyrate modulates the expression of genes encoding short-chain fatty acid (SCFA) transporters (Slc16a1, Slc16a3, Slc16a4, Slc5a8, Abcg2) and receptors (Hcar2, Ffar2, Ffar3, Olfr78, Olfr558) in the colon, (2) the potential involvement of gut microbiota in this modulation, and (3) the impact of oral butyrate on the expression of colonic SCFA transporters and receptors during colonic inflammation. Specific pathogen-free (SPF) and germ-free (GF) mice with or without DSS-induced inflammation were provided with either water or a 0.5% sodium butyrate solution. The findings revealed that butyrate decreased the expression of Slc16a1, Slc5a8, and Hcar2 in SPF but not in GF mice, while it increased the expression of Slc16a3 in GF and the efflux pump Abcg2 in both GF and SPF animals. Moreover, the presence of microbiota was associated with the upregulation of Hcar2, Ffar2, and Ffar3 expression and the downregulation of Slc16a3. Interestingly, the challenge with DSS did not alter the expression of SCFA transporters, regardless of the presence or absence of microbiota, and the effect of butyrate on the transporter expression in SPF mice remained unaffected by DSS. The expression of SCFA receptors was only partially affected by DSS. Our results indicate that (1) consuming a relatively low concentration of butyrate can influence the expression of colonic SCFA transporters and receptors, with their expression being modulated by the gut microbiota, (2) the effect of butyrate does not appear to result from direct substrate-induced regulation but rather reflects an indirect effect associated with the gut microbiome, and (3) acute colon inflammation does not lead to significant changes in the transcriptional regulation of most SCFA transporters and receptors, with the effect of butyrate in the inflamed colon remaining intact.

Department of Physiology Faculty of Science Charles University Prague Czechia

Institute of Microbiology Czech Academy of Sciences Nový Hrádek Czechia

Institute of Physiology Czech Academy of Sciences Prague Czechia

Zobrazit více v PubMed

Akiba Y., Inoue T., Kaji I., Higashiyama M., Narimatsu K., Iwamoto K., et al. (2015). Short-chain fatty acid sensing in rat duodenum. J. Physiol. 593, 585–599. 10.1113/jphysiol.2014.280792 PubMed DOI PMC

Al-Mosauwi H., Ryan E., McGrane A., Riveros-Beltran S., Walpole C., Dempsey E., et al. (2016). Differential protein abundance of a basolateral MCT1 transporter in the human gastrointestinal tract. Cell Biol. Int. 40, 1303–1312. 10.1002/cbin.10684 PubMed DOI

Borthakur A., Saksena S., Gill R. K., Alrefai W. A., Ramaswamy K., Dudeja P. K. (2008). Regulation of monocarboxylate transporter 1 (MCT1) promoter by butyrate in human intestinal epithelial cells: involvement of NF-κB pathway. J. Cell. Biochem. 103, 1452–1463. 10.1002/jcb.21532 PubMed DOI PMC

Chen G., Ran X., Li B., Li Y., He D., Huang B., et al. (2018). Sodium butyrate inhibits inflammation and maintains epithelium barrier integrity in a TNBS-induced inflammatory bowel disease mice model. EBioMedicine 30, 317–325. 10.1016/j.ebiom.2018.03.030 PubMed DOI PMC

Cresci G. A., Thangaraju M., Mellinger J. D., Liu K., Ganapathy V. (2010). Colonic gene expression in conventional and germ-free mice with a focus on the butyrate receptor GPR109A and the butyrate transporter SLC5A8. J. Gastrointest. Surg. 14, 449–461. 10.1007/s11605-009-1045-x PubMed DOI

Dalile B., Van Oudenhove L., Vervliet B., Verbeke K. (2019). The role of short-chain fatty acids in microbiota-gut-brain communication. Nat. Rev. Gastroenterol. Hepatol. 16, 461–478. 10.1038/s41575-019-0157-3 PubMed DOI

Daniel P., Brazier M., Cerutti I., Pieri F., Tardivel I., Desmet G., et al. (1989). Pharmacokinetic study of butyric acid administered in vivo as sodium and arginine butyrate salts. Clin. Chim. Acta. 181, 255–263. 10.1016/0009-8981(89)90231-3 PubMed DOI

Dengler F., Rackwitz R., Benesch F., Pfannkuche H., Gäbel G. (2015). Both butyrate incubation and hypoxia upregulate genes involved in the ruminal transport of SCFA and their metabolites. J. Anim. Physiol. Anim. Nutr. Berl. 99, 379–390. 10.1111/jpn.12201 PubMed DOI

Dou X., Gao N., Yan D., Shan A. (2020). Sodium butyrate alleviates mouse colitis by regulating gut microbiota dysbiosis. Anim. (Basel) 10, 1154. 10.3390/ani10071154 PubMed DOI PMC

Erdmann P., Bruckmueller H., Martin P., Busch D., Haenisch S., Müller J., et al. (2019). Dysregulation of mucosal membrane transporters and drug-metabolizing enzymes in ulcerative colitis. J. Pharm. Sci. 108, 1035–1046. 10.1016/j.xphs.2018.09.024 PubMed DOI

Facchin S., Vitulo N., Calgaro M., Buda A., Romualdi C., Pohl D., et al. (2020). Microbiota changes induced by microencapsulated sodium butyrate in patients with inflammatory bowel disease. Neurogastroenterol. Motil. 32, e13914. 10.1111/nmo.13914 PubMed DOI PMC

Gaudier E., Rival M., Buisine M.-P., Robineau I., Hoebler C. (2009). Butyrate enemas upregulate Muc genes expression but decrease adherent mucus thickness in mice colon. Physiol. Res. 58, 111–119. 10.33549/physiolres.931271 PubMed DOI

Gill R. K., Saksena S., Alrefai W. A., Sarwar Z., Goldstein J. L., Carroll R. E., et al. (2005). Expression and membrane localization of MCT isoforms along the length of the human intestine. Am. J. Physiol. Cell Physiol. 289, C846–C852. 10.1152/ajpcell.00112.2005 PubMed DOI

Gonçalves P., Araújo J. R., Di Santo J. P. (2018). A cross-talk between microbiota-derived short-chain fatty acids and the host mucosal immune system regulates intestinal homeostasis and inflammatory bowel disease. Inflamm. Bowel Dis. 24, 558–572. 10.1093/ibd/izx029 PubMed DOI

Gonçalves P., Gregório I., Martel F. (2011). The short-chain fatty acid butyrate is a substrate of breast cancer resistance protein. Am. J. Physiol. Cell Physiol. 301, C984–C994. 10.1152/ajpcell.00146.2011 PubMed DOI

Graham D. B., Xavier R. J. (2020). Pathway paradigms revealed from the genetics of inflammatory bowel disease. Nature 578, 527–539. 10.1038/s41586-020-2025-2 PubMed DOI PMC

Gurav A., Sivaprakasam S., Bhutia Y. D., Boettger T., Singh N., Ganapathy V. (2015). Slc5a8, a Na+-coupled high-affinity transporter for short-chain fatty acids, is a conditional tumour suppressor in colon that protects against colitis and colon cancer under low-fibre dietary conditions. Biochem. J. 469, 267–278. 10.1042/BJ20150242 PubMed DOI PMC

Halperin Kuhns V. L., Sanchez J., Sarver D. C., Khalil Z., Rajkumar P., Marr K. A., et al. (2019). Characterizing novel olfactory receptors expressed in the murine renal cortex. Am. J. Physiol. Ren. Physiol. 317, F172–F186. 10.1152/ajprenal.00624.2018 PubMed DOI PMC

Han R., Ma Y., Xiao J., You L., Pedisić S., Liao L. (2021). The possible mechanism of the protective effect of a sulfated polysaccharide from Gracilaria lemaneiformis against colitis induced by dextran sulfate sodium in mice. Food Chem. Toxicol. 149, 112001. 10.1016/j.fct.2021.112001 PubMed DOI

Hausmann M., Leucht K., Ploner C., Kiessling S., Villunger A., Becker H., et al. (2011). BCL-2 modifying factor (BMF) is a central regulator of anoikis in human intestinal epithelial cells. J. Biol. Chem. 286, 26533–26540. 10.1074/jbc.M111.265322 PubMed DOI PMC

Hou G., Yin J., Wei L., Li R., Peng W., Yuan Y., et al. (2022). Lactobacillus delbrueckii might lower serum triglyceride levels via colonic microbiota modulation and SCFA-mediated fat metabolism in parenteral tissues of growing-finishing pigs. Front. Vet. Sci. 9, 982349. 10.3389/fvets.2022.982349 PubMed DOI PMC

Hudcovic T., Štĕpánková R., Cebra J., Tlaskalová-Hogenová H. (2001). The role of microflora in the development of intestinal inflammation: acute and chronic colitis induced by dextran sulfate in germ-free and conventionally reared immunocompetent and immunodeficient mice. Folia Microbiol. (Praha) 46, 565–572. 10.1007/BF02818004 PubMed DOI

Ji J., Shu D., Zheng M., Wang J., Luo C., Wang Y., et al. (2016). Microbial metabolite butyrate facilitates M2 macrophage polarization and function. Sci. Rep. 6, 24838. 10.1038/srep24838 PubMed DOI PMC

Jourova L., Satka S., Frybortova V., Zapletalova I., Anzenbacher P., Anzenbacherova E., et al. (2022). Butyrate treatment of DSS-induced ulcerative colitis affects the hepatic drug metabolism in mice. Front. Pharmacol. 13, 936013. 10.3389/fphar.2022.936013 PubMed DOI PMC

Kaji I., Iwanaga T., Watanabe M., Guth P. H., Engel E., Kaunitz J. D., et al. (2015). SCFA transport in rat duodenum. Am. J. Physiol. Gastrointest. Liver Physiol. 308, G188–G197. 10.1152/ajpgi.00298.2014 PubMed DOI PMC

Kim H.-J., An J., Ha E.-M. (2022). Lactobacillus plantarum-derived metabolites sensitize the tumor-suppressive effects of butyrate by regulating the functional expression of SMCT1 in 5-FU-resistant colorectal cancer cells. J. Microbiol. 60, 100–117. 10.1007/s12275-022-1533-1 PubMed DOI

Kim M. H., Kang S. G., Park J. H., Yanagisawa M., Kim C. H. (2013). Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology 145, 396–406. 10.1053/j.gastro.2013.04.056 PubMed DOI

Kotlo K., Anbazhagan A. N., Priyamvada S., Jayawardena D., Kumar A., Chen Y., et al. (2020). The olfactory G protein-coupled receptor (Olfr-78/OR51E2) modulates the intestinal response to colitis. Am. J. Physiol. Cell Physiol. 318, C502–C513. 10.1152/ajpcell.00454.2019 PubMed DOI PMC

Larraufie P., Martin-Gallausiaux C., Lapaque N., Dore J., Gribble F. M., Reimann F., et al. (2018). SCFAs strongly stimulate PYY production in human enteroendocrine cells. Sci. Rep. 8, 74. 10.1038/s41598-017-18259-0 PubMed DOI PMC

Laserna-Mendieta E. J., Clooney A. G., Carretero-Gomez J. F., Moran C., Sheehan D., Nolan J. A., et al. (2018). Determinants of reduced genetic capacity for butyrate synthesis by the gut microbiome in Crohn’s disease and ulcerative colitis. J. Crohns Colitis 12, 204–216. 10.1093/ecco-jcc/jjx137 PubMed DOI

Lee C., Kim B. G., Kim J. H., Chun J., Im J. P., Kim J. S. (2017). Sodium butyrate inhibits the NF-kappa B signaling pathway and histone deacetylation, and attenuates experimental colitis in an IL-10 independent manner. Int. Immunopharmacol. 51, 47–56. 10.1016/j.intimp.2017.07.023 PubMed DOI

Lee J. G., Lee J., Lee A.-R., Jo S. V., Park C. H., Han D. S., et al. (2022). Impact of short-chain fatty acid supplementation on gut inflammation and microbiota composition in a murine colitis model. J. Nutr. Biochem. 101, 108926. 10.1016/j.jnutbio.2021.108926 PubMed DOI

Lin Y., Lv Y., Mao Z., Chen X., Chen Y., Zhu B., et al. (2023). Polysaccharides from Tetrastigma hemsleyanum Diels et Gilg ameliorated inflammatory bowel disease by rebuilding the intestinal mucosal barrier and inhibiting inflammation through the SCFA-GPR41/43 signaling pathway. Int. J. Biol. Macromol. 250, 126167. 10.1016/j.ijbiomac.2023.126167 PubMed DOI

Machiels K., Joossens M., Sabino J., De Preter V., Arijs I., Eeckhaut V., et al. (2014). A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut 63, 1275–1283. 10.1136/gutjnl-2013-304833 PubMed DOI

Macia L., Tan J., Vieira A. T., Leach K., Stanley D., Luong S., et al. (2015). Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat. Commun. 6, 6734. 10.1038/ncomms7734 PubMed DOI

Nan X., Zhao W., Liu W.-H., Li Y., Li N., Hong Y., et al. (2023). Bifidobacterium animalis subsp. lactis BL-99 ameliorates colitis-related lung injury in mice by modulating short-chain fatty acid production and inflammatory monocytes/macrophages. Food Funct. 14, 1099–1112. 10.1039/d2fo03374g PubMed DOI

Ni J., Wu G. D., Albenberg L., Tomov V. T. (2017). Gut microbiota and IBD: causation or correlation? Nat. Rev. Gastroenterol. Hepatol. 14, 573–584. 10.1038/nrgastro.2017.88 PubMed DOI PMC

Nishida A., Miyamoto J., Shimizu H., Kimura I. (2021). Gut microbial short-chain fatty acids-mediated olfactory receptor 78 stimulation promotes anorexigenic gut hormone peptide YY secretion in mice. Biochem. Biophys. Res. Commun. 557, 48–54. 10.1016/j.bbrc.2021.03.167 PubMed DOI

Priori D., Colombo M., Clavenzani P., Jansman A. J. M., Lallès J.-P., Trevisi P., et al. (2015). The olfactory receptor OR51E1 is present along the gastrointestinal tract of pigs, co-localizes with enteroendocrine cells and is modulated by intestinal microbiota. PLoS One 10, e0129501. 10.1371/journal.pone.0129501 PubMed DOI PMC

Priyadarshini M., Kotlo K. U., Dudeja P. K., Layden B. T. (2018). Role of short chain fatty acid receptors in intestinal physiology and pathophysiology. Compr. Physiol. 8, 1091–1115. 10.1002/cphy.c170050 PubMed DOI PMC

Recharla N., Geesala R., Shi X.-Z. (2023). Gut microbial metabolite butyrate and its therapeutic role in inflammatory bowel disease: a literature review. Nutrients 15, 2275. 10.3390/nu15102275 PubMed DOI PMC

Satka S., Frybortova V., Zapletalova I., Anzenbacher P., Anzenbacherova E., Kozakova H., et al. (2022). Effect of DSS-induced ulcerative colitis and butyrate on the cytochrome P450 2A5: contribution of the microbiome. Int. J. Mol. Sci. 23, 11627. 10.3390/ijms231911627 PubMed DOI PMC

Thibault R., De Coppet P., Daly K., Bourreille A., Cuff M., Bonnet C., et al. (2007). Down-regulation of the monocarboxylate transporter 1 is involved in butyrate deficiency during intestinal inflammation. Gastroenterology 133, 1916–1927. 10.1053/j.gastro.2007.08.041 PubMed DOI

Vieira E. L. M., Leonel A. J., Sad A. P., Beltrão N. R. M., Costa T. F., Ferreira T. M. R., et al. (2012). Oral administration of sodium butyrate attenuates inflammation and mucosal lesion in experimental acute ulcerative colitis. J. Nutr. Biochem. 23, 430–436. 10.1016/j.jnutbio.2011.01.007 PubMed DOI

Wang R., Cao S., Bashir M. E. H., Hesser L. A., Su Y., Hong S. M. C., et al. (2023). Treatment of peanut allergy and colitis in mice via the intestinal release of butyrate from polymeric micelles. Nat. Biomed. Eng. 7, 38–55. 10.1038/s41551-022-00972-5 PubMed DOI PMC

Yajima M., Karaki S.-I., Tsuruta T., Kimura S., Nio-Kobayashi J., Kuwahara A., et al. (2016). Diversity of the intestinal microbiota differently affects non-neuronal and atropine-sensitive ileal contractile responses to short-chain fatty acids in mice. Biomed. Res. 37, 319–328. 10.2220/biomedres.37.319 PubMed DOI

Zhang S., Xu W., Wang H., Cao M., Li M., Zhao J., et al. (2019). Inhibition of CREB-mediated ZO-1 and activation of NF-κB-induced IL-6 by colonic epithelial MCT4 destroys intestinal barrier function. Cell Prolif. 52, e12673. 10.1111/cpr.12673 PubMed DOI PMC

Ziegler K., Kerimi A., Poquet L., Williamson G. (2016). Butyric acid increases transepithelial transport of ferulic acid through upregulation of the monocarboxylate transporters SLC16A1 (MCT1) and SLC16A3 (MCT4). Arch. Biochem. Biophys. 599, 3–12. 10.1016/j.abb.2016.01.018 PubMed DOI PMC